3,6-dimethyl - 1,2,3,4,4a,9a - hexahydro-ypsilon-carboline dihydrochloride for treating mental diseases

ABSTRACT

A MEDICINAL PREPARATION HAVING A PSYCHOTROPIC EFFECT FOR TREATING MENTAL DISEASES SUCH AS SCHIZOPHRENIA; ALCOHOLIC PSYCHOSES, AND SYNDROMUM ABSTINTENTIA. THE PREPARATION COMPRISES AS ITS ACTIVE PRINCIPLE 3,6-DIMETHYL1,2,3,4,4A,9A-HEXAHYDRO-Y-CARBOLINE DIHYDROCHLORIDE OF THE FORMULA   2,8-DI(CH3-)-1,2,3,4,4A,9B-HEXAHYDRO-5H-PYRIDO(4,3-B)-   INDOLE (HCL)2   THE MEDICINAL PREPARATION CAN BE PREPARED AS A POWDER, TABLET OR INJECTION SOLUTION.

United States Patent @tfic 3,743,740 Patented July 3, 1973 3,6 DIMETHYL 1,2,3,4,4a,9a HEXAHYDRO-y- CARBOLINE DIHYDROCHLORIDE FOR TREAT- ING MENTAL DISEASES Nikolai Konstantinovich Barkov, Belyaevo-Bogorodskoe, kvartal 46-47, korpus 40, kv. 160; Ntalya Fedorovna Kucherova, Petroverigsky perulok 3, kv. 21; Nikolai Konstantinovich Kochetkov, Leninsky prospekt 13, kv. 129; Izida Grigorievna Zhukova, Konkovo-Derevlevo 6, mikroraion, korpus 27, kv. 78; and Nina Mikhailovna Sjhgrnga, 3 Denskoi proezd 5, kv. 22, all of Moscow,

No Drawing. Original application Oct. 31, 1968, Ser. No. 873,096, now Patent No. 3,657,254, dated Apr. 18, 1972. Divided and this application Dec. 16, 1971, Ser.

Int. Cl. A61k 27/00 US. Cl. 424-267 5 Claims ABSTRACT OF THE DISCLOSURE A medicinal preparation having a psychotropic effect eifect for treating mental diseases such as schizophrenia; alcoholic psychoses, and syndromum abstintentia. The preparation comprises as its active principle 3,6-dimethyl- 1,2,3,4,4a,9a-hexahydro-v-carboline dihydrochloride of the formula The medicinal preparation can be prepared as a powder, tablet or injection solution.

This application is a division of application Ser. No. 873,096 filed Oct. 31, 1968 and issued as US. Pat. 3,657,- 254 on Apr. 18, 1972.

The present invention relates to a medicinal preparation comprising as an active principle 3,6-dimethyl-l,2,3, 4,4a,9a-hexahydro-v-carboline dihydrochloride.

According to the invention, 3,6-dimethyl-1,2,3,4,4a,9ahexahydro- -carboline dihydrochloride has the following formula This compound is a crystalline substance of white colour with a slightly creamish tint and is readily soluble in water. Its M.P. 274-276 C.

3,6 dimethyl 1,2,3,4,4a,9a-hexahydro-7-carboline dihydrochloride is produced by reducing 3,6-dimethy1-1,2,3- 4-tetrahydro- -carboline hydrochloride in an aqueousacidic medium at a temperature of up to 100 C. with subsequent alkalization of the reaction mixture, separation of the resulting base, 3,6-dimethyl-1,2,3,4,4a,9a-hexahydro-v-carboline, treatment of the base with hydrogen chloride and isolation of the product. I

It is preferable to use amalgamated zinc or tin as a reducing agent.

It is preferable to use an aqueous hydrochloric medium as an aqueous-acidic medium.

The method is effected as follows.

3,6-dimethyl-1,2,3,4-tetrahydro 'y carboline hydrochloride is dissolved in water, and a reducing agent, namely, amalgamated zinc or tin, is added to the solution, the reaction mixture is heated to 100 C., and concentrated hydrochloric or sulphuric acid, preferably hydrochloric acid, is introduced dropwise into the mixture with stirring. The mixture is heated for 4.5-6 hours. The reducing agent and acid are introduced in several batches. Then an alkali is introduced into the reaction mixture (with the mixture being cooled with ice to a temperature not above 15 C.), and the obtained base, that is, 3,6-dimethyl-l,2,3,4,4a,9a-hexahydro-y-carboline, is extracted with ether. The ethereal extracts are dried with magnesium sulphate, the ether is distilled off, and the residue is treated with hydrogen chloride, the resulting product being 3,6-dimethyl 1,2,3,4,4a,9a hexahydro-v-carboline dihydrochloride. The yield is 60-72%. The M.P. of the product is 274-276 C.

3,6-dimethyl 1,2,3,4,4a,9a hexahydro 'y carboline dihydrochloride has been established as having pharmacological activity and may be used as an active principle of a medicinal preparation.

According to the present invention a medicinal preparation having a psychotropic effect includes 3,6-dimethyl- 1,2,3,4,4a,9a-hexahydro-y-carboline dihydrochloride as an active principle. The medicinal preparation which we will hereinafter be called carbidine, may according to the invention contain an active principle in combination with a pharmaceutic filler for tablets, or a diluent for injection solutions. The preparation is one of venene B and has a psychotropic effect. The mechanism of action of the preparation is associated with its negative influence on adrenorgic structures (adreno-blocking action and hindrance to the return of free noradrenalin from the extracellular space).

The effect produced by carbidine becomes rapidly manifested, often after a single administration. This effect is characterized by a number of specific features: by a combination of neuroleptic, antidepressive and energizing results, as well as by taking place only with respect to definite syndromes and states of the patient.

Carbidine proves to be effective for treating mental diseases, such as paranoiac depression in case of schizophrenia, affective delusions in simple schizophrenia, and also for treating patients suffering from alcoholic psychoses and syndromum abstinentiae.

Carbidine has passed clinical tests on 650 patients. In the case of depressive paranoiac form of schizophrenia, a favorable symptom for treating patients with the present preparation was as follows: a manifest acuteness of the state with a sudden commencement of the attack, fear, anxiety, massive and intense sensations of disquietude, often imminent to life, as Well as predominance of sensory delusions over the affective ones with a manifest Kandinksy-Clrambault, syndrome that has a pronounced sensory character.

The administration of the present preparation has resulted in the sedation of patients, regression of sensory delusion and hallucinations, spychic automatisms with a simultaneous diminution of depression profundity and general activation of patients. Sometimes the effect of the preparation proves to be fulminant, with exit of the patient from the state of mental depression after 4-7 days.

In the case of depressive-paranoiac schizophenia, the preparation is administered per os or by intramuscular injection, starting with a dose of -25 mg. and increasing it up to 75-100 mg., even to mg., in fractional doses 3 times a day.

Should the convalescence effect with the preparation administered in a dose up to 150 mg. per day diminish, it is recommended to reduce the dose to 75-50 mg., which will hasten further improvement of the state of patients.

The effect of carbidine in the case of cyclic schizophrenia with depressive-paranoiac structure, the eifect is similar to that described hereinabove. In other periodic forms of schizophrenia (oneuroidal catatony, acute paraphrenia) the preparation is effective when depressivedelirium phenomena are present in the clinical picture. Carbidine produces positive results when the depression states of the patients originate in a simple form, or in the case of more profound states accompanied by a certain degree of embarrassment, derealization and mental derangements, or, else, in case of prolonged subdepressive states with the patient experiencing feelings of becoming altered, obtusion, or, still, in case of almost continuous affective fluctuations with symptoms of depression and dysphophia, discontent, and irritability. For treating affective disorders Within a simple form, the preparation is applied starting with a dose of 12.5 mg. with a gradual increase of the dosage up to 75-100 mg, sometimes, when necessary, in combination with imipramine. Carbidine produces a rapid therapeutic effect in treating acute alcoholic paranoia and acute hallucinosis.

When treating alcoholic psychoses, the preparation is administered in the form of intramuscular injections in doses of 50 mg. with an interval of 2 hours (up to 3-4 injections), and then 3 times a day, or 3 times a day from the start.

The preparation is effective when treating milder forms of delirium with a relatively non-manifest excitation, with no massive hallucinatory experiences, and with a predominance of illusory disorders.

A positive result of carbidine has also been observed in cases of syndromum abstinentiae, where its administration has resulted in the disappearance of illusory disorders and vegetative function disturbances.

The carbidine preparation may be applied in the form of powders, tablets of 25 mg. each, and as injection solutions containing 1.25 Wt. percent of the active principle.

The dosage of the preparation depends on the different psychopathological state of the patient. Most often an initial dose of 12.5 mg. proves to be suitable, with subsequent increase to 75-100, even to 150 mg.

The preparation is contraindicated for functional disturbances of the lever and for intoxications with narcotics and analgetics, since carbidine potentiates the effects of narcotics and analgetics.

Side effects of the carbidine preparation are insignificant. Sometimes tremor subtilis may be observed, especially in the upper extremities of a patient, constraint and higher muscular tonus, as well as hyperkineses inexpressivae. In certain cases correctors can be prescribed (such as arthane and the like).

For a better understanding of the method of producing 3,6-dimethyl-l,2,3,4,4a,9a-hexahydro 'y carboline dihydrochloride, the following examples are given.

EXAMPLE 1 165.7 g. of 3,6-dimethyl-1,2,3,4-tetrahydro-v-carboline hydrochloride are dissolved in 150' ml. of water, then 198 g. of zinc dust and 0.25 g. of mercuric chloride are added thereto, and the reaction mixture is heated to 60-80 C. Then 990 ml. of concentrated hydrochloric acid are introduced dropwise with stirring, and the reaction mixture is heated for 1.5-2 hours.

The addition of zinc dust and hydrochloric acid is repeated twice again in the same amounts and during the same period of time. Then an excess of 45-50% concentration solution of caustic soda is introduced into the reaction mixture, after which it is cooled with ice to a temperature not above +15 C., and the resulting base, which is 3,6-dimethyl-l,2,3,4,4a,9a-hexahydro-'ycarboline, is extracted with 6.6 l. of ether (by using 1.65 l. of ether 4 times). The ethereal extracts are dried with magnesium sulphate, of the ether is distilled off, and a 25% alcoholic solution of hydrogen chloride is added to the residue for the reaction to be acidic (pH=5.0- 4.0). The precipitation is filtered off. The yield of the product is 138 g. (72%). MP. is 274276 C.

Found (percent): C, 56.91; 56.88; H, 5.23; 7.25; N, 9.85; 9.66; Cl, 25.62; 25.59; C H N Cl Calculated (percent): C, 56.73; H, 7.32; N, 10.18; C1, 25.76.

EXAMPLE 2 8.3 g. of 3,6-dimethyl-1,2,3,4-tetrahydro- -carbo1ine hydrochloride are dissolved in 75 ml. of water, and 160 g. of granulated tin and 100 ml. of concentrated hydrochloric acid are added thereto. The reaction mixture is boiled 1.5-2 hours. Hydrochloric acid is added two more times in the same amounts, and boiling is effected during the same period of time. The reaction mixture obtained is filtered.

The process of alkaline treatment, extraction of the base and isolation of the product is carried out in the same manner as described in Example 1, 57 g. of the product being obtained (60%). MP. 274-276 C. (from ethyl alcohol).

What is claimed is:

1. A medicinal preparation having a pyschotropic effect for the treatment of mental diseases, alcoholic psychoses, and syndromum abstinentiae, said preparation, comprising a pharmaceutical carrier and as an active principle an effective amount of 3,6-dimethyl-1,2,3,4,4a,9a-hexadro-y-carboline dihydrochloride of the formula 2. A medicinal preparation according to claim 1, wherein the carrier is a pharmaceutic filler for forming the preparation as a tablet.

3. A medicinal preparation according to claim 2, wherein the active principle is present in an amount of 1.25% by weight.

4. A medicinal preparation according to claim 1, wherein the carrier is a solvent for forming the preparation in an injection solution.

5. A medicinal preparation according to claim 4, wherein the active principle is present in an amount of 1.25 by weight.

References Cited Kochetkov et al.: Zhur, Obschchey Khim. 31, 924-30 (1961).

STANLEY J. FRIEDMAN, Primary Examiner 

